Alpha-nitro-cinnamic acid derivatives

ABSTRACT

Alpha -nitro-cinnamic acid derivatives which are useful in preparing phenylalanines, and a process for obtaining the derivatives by treating the corresponding cinnamic acid esters with nitric oxide or nitrogen dioxide.

United States Patent [191 Krubiner et al.

[451 Aug. 27, 1974 ALPHA-NlTRO-CINNAMIC ACID DERIVATIVES Inventors: Alan Martin Krubiner, Montville; Eugene Paul Oliveto, Glen Ridge,

both of NJ.

Assignee: Hoffman-La Roche Inc., Nutley,

Filed: Mar. 16, 1972 Appl. No: 235,421

US. Cl. 260/471 A, 260/476 R, 260/479 R, 260/518 R, 260/519, 260/521 R Int. Cl. C07c 79/46 Field of Search 260/471 A, 521 R, 479 R, A

[56] References Cited UNITED STATES PATENTS 3,488,363 1/1970 Hinkley 260/47l A Primary Examiner-Lorraine A. Weinberger Assistant Examiner-L. A. Thaxton Attorney, Agent, or FirmSamuel L. Welt; Jon S. Saxe; William H. Epstein 7 Claims, No Drawings ALPHA-NITRO-CINNAMIC ACID DERIVATIVES SUMMARY 'oF THE lNVENTlON ln accordance with this invention, it has been found that compounds of the formula:

wherein R, and R' are hydrogen or hydroxy or a conventional group convertible to a hydroxy group by hydrolysis; and Y is a conventional group convertible to a carboxy group by hydrolysis; with the proviso that R, and R' are not both hydroxy;

are obtained by treating cinnamic acid esters of the formula:

wherein R and R-; and Y are as above; with nitric oxide or nitrogen dioxide.

The compounds of formula I, wherein R and R are both hydroxy and/or Y is carboxy can be obtained by hydrolysis of the compound of formula lA wherein R, and R' are hydroxy or a conventional group convertible to a hydroxy group by hydrolysis.

DETAILED DESCRIPTION OF THE INVENTION As used throughout this application, the term lower alkyl" comprehends both straight chain and branched chain saturated alkyl hydrocarbon groups containing from one to seven carbon atoms, such as methyl, ethyl and isopropyl.

The term aryl, as used herein, signifies mononuclear aromatic hydrocarbon groups such as phenyl and tolyl which can beunsubstituted or substituted in one or more positions with a halogen, a nitro, a lower alkyl or a lower alkoxy substituent, and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl and azulyl which can be substituted with one or more of the aforementioned groups. The preferred aryl groups are the substituted and unsubstituted mono-nuclear groups, particularly phenyl. The term aryl lower alkyl comprehends groups wherein aryl and lower alkyl are as defined above. The preferred aryl lower alkyl group is benzyl.

As also used throughout this application, the term lower alkoxy comprehends alkoxy groups containing from one to seven carbon atoms, such as methoxy, propoxy, ethoxy, etc. As also used herein, the term lower alkanoic acid comprehends both straight chainand branched chain alkanoic acids containing from one to seven carbon atoms, such as formic and acetic acids, preferably acetic acid. As further used herein, the term aryl lower alkanoic acids comprehends acids wherein aryl and lower alkanoic are as defined above, preferably benzoic acid.v As still further used herein, the term acyl comprehends lower alkanoyl and monocyclic aroyl groups such as formyl, acetyl and benzoyl.

In this application, the term lower alkanol comprehends alkanols of one to seven carbon atoms, such as methanol and isopropanol. As used herein, the term aryl lower alkanol comprehends groups wherein aryl and lower alkanol are as defined above, preferably benzyl alcohol. Also herein, the term allylic comprehends allyl groups which may be unsubstituted or substituted on the 3-carbon by a lower alkyl group, such as 2-butenyl and 2-propenyl. Asfurther used herein, the term nitric oxide comprehends the compound: NO. As used herein, the term nitrogen dioxide" comprehends the compound: N0 as well as the higher aggregates thereof: (N0 wherein x is an integer of from 1 to 4, such as N 0 As further used throughout this application, the term conventional group convertible to a carboxy group by hydrolysis comprehends an ester group which can be hydrolyzed to regenerate a carboxy group. In this application, any conventional ester groupthat can be hydrolyzed to regenerate the carboxy group can be utilized. Exemplary esters useful for this purpose are the lower alkyl, aryl, and aryl lower alkyl esters.

As still further used throughout this application, the term conventional group convertible to a hydroxy group by hydrolysis comprehends an ester group or an ether group which can be hydrolyzed to regenerate a hydroxy group. In this application, any ester or ether group that can be hydrolyzed to yield the hydroxy group can be utilized. Exemplary ester groups useful for this purpose are those in which the acyl moiety is derived from a lower alkanoic, an aryl lower alkanoic, phosphoric, carbonic or a lower alkane dicarboxylic acid. Exemplary ether groups useful for this purpose are the tetrahydropyranyl, aryl lower alkyl, lower alkyl, a-loweralkoxy-lower alkyl and allylic ethers, as well as the methylene diether.

Among the preferred compounds of formula I are the compounds of the formula:

wherein R"; and R g are hydroxy or conventional group convertible to a hydroxy group by hydroly' whichcan be, reduced to phenylalanines that are useful i 'in preparing compounds having anti-Parkinsonsactivity. Particularly preferred a are the compounds? of the 1 formula:

icaLand the rea'ctioncan be cani'edout at room temperature and atmospheric pressure. {Pr'efe'rably, a: t'em-' perature of aboutfOCu tothej'refiuxtemperature-of the w mixture is utilized with the reflux temperature 1 reaction being particularly-preferred The a-nitrocinna'rnic acids I and R are both hydroxy and/or'Y is carboxy, can be .obtained by -hydrolyzing.the'corresponding:or-nitro cininamic; acid'esters fformuia I -A, whereinv R and R ,Qare-hydroxy"ora'coi ventipnall group convertible to a l 1 y xg P5b' i drpl i n r y ng i tthis hyd' va 1 .lysis,. any conventionalfmethodofhydrolysis can be. ;uti-. i

-j lized. Preferably; hydrolysiswitha'base,lparticularly' an I 5 wherein Y is as above and R and R are hydroxy, lower alkoxy, lower alkanoyloxy, or benzoyloxy, 1 In accordance with the-process of this invention, the

. a-nitro compound of formula l-A can be obtained by treating the compound of formula II with nitric oxide without the formation of appreciable amounts of other nitro compounds. In carrying out this. reaction, any

conventionalinert' organic solvent canv be utilized; Among the preferred solvents are the chlorinated aliphatic and aromatic hydrocarbons such as carbon tet-, rachloride. In this reaction. temperature and pressure ornitrogen dioxide in an inert solvent. lt hasbeen 'surj prisingly found that by'the process of this invention,

a-nitro cinnamic acid esters are selectively produced a are not critical. and the reaction can be conveniently I carried out at a temperature of about 0C. to the reflux temperature of the reaction mixture and at atmospheric pressure. Preferably.- thereaction is carried out at room temperature (22C.).

The cinnamic acid esters of formula ll can be obtained by treating a compound of the formula:

wherein R, and R, are as above;

' R is hydrogen or acyl:

alkali metal; hydroxidefis uch as sodium hydroxide, is; I utilized 3 l M a v The compounds of 'formul-alj can bereduced by hydrogenation, preferably catalytic hydrogenation, to the corresponding -phenylalanin'esof the formula:

" wherein R1, R Y areas above and i It I 3 In the catalytic hydrogenation:of the compound of formula I, any conventionalhydrogenation catalystcan be utili zed,such as palladium, Raney-nickel or platinum, with palladiumbeing preferred. Thehydrogenationre f' action can be carried out inan inert solvent.- In this reaction, any conventional inert solvent can be utilized, such as a loweralkanol Preferably, hydrogenation is carried out in an acid which 'willform a salt with'the amineas it is formed. It is particularly preferred that the acid medium have a pH of 1-5. Preferred acids are the mineral acids, particularly HCl, the lower alkanoic acids, particularly acetic acid, and the 'sulfonic acids, particularly the lower alkylsulfonic acids and toluene sulfonic acids, with the lower alkanoic acids being particularly preferred. In-the hydrogenation of the com pound of formula I, temperature and pressure are not critical, and the reaction can be carried out at room temperature and atmospheric pressure. Preferably, hydrogenation is carried out at a temperature of 10C. .to

C. and a pressure of 1 to 3 atm. When hydrogenation is carried out in an acid medium, the corresponding salt of the phenylalanines of formula IV, wherein R is hydrogen, is obtained.

of formula I, wherein R I I The catalytic hydrogenation of the compound of formula l is also preferably carried out in the presence of an acid anhydride, which provides an N-acyl substituent (R on the phenylalanines of formula IV. Any conventional acid anhydride which provides an N-acyl group can be utilized. Preferred acid anhydrides include the lower alkanoic and benzoic acid anhydrides, particularly acetic anhydride.

The following examples illustrate the invention. All temperatures are stated in degrees Centrigrade.

Example 1 A mixture of 166 g of veratraldehyde, 1 14.4 g of malonic acid, 250 ml of 95 percent ethanol and ml of pyridine was refluxed for 8 hours, cooled and filtered to afford 66 g of 3,4-dimethoxycinnamic acid; m.p. l67l70C. This was refluxed overnight with l l. of ethanol containing 14 ml of concentrated hydrochloric acid, evaporated to dryness and the residue dissolved in diethyl ether, washed with water and the ether dried and evaporated to afford 75.7 g of crude ester. After recrystallization from diethyl ether-petroleum ether, there was obtained ethyl 3,4-dimethoxycinnamate.

Example 2 A mixture of 75.0 g of vanillin, 156 g of malonic acid, 210 ml of pyridine and 6 ml of piperidine was heated on a steam bath for 1.5 hours, cooled and poured into a mixture of 255 ml of concentrated hydrochloric acid and 300 g of ice. The precipitated material was filtered and recrystallized from 2 l. of water to afford 55 g of 3-methoxy-4-hydroxycinnamic acid; m.p. l72l74. This was heated at reflux overnight with 825 ml of ethanol and 16.5 ml of concentrated hydrochloric acid and evaporated to dryness, and the residue was dissolved in diethyl ether. The ether was washed with water, dried and evaporated and the residue was recrystallized from diethyl ether-petroleum ether to afford 54.8 g of ethyl 3-methoxy-4-hydroxycinnamate; m.p. 5759. This material (25.0 g) was dissolved in a mixture of 50 ml of acetic anhydride and 100 ml of pyridine and allowed to stand at room temperature overnight. After quenching in ice-water, the precipitated product was filtered to yield ethyl 3-methoxy-4-acetoxycinnamate; m.p. l l8-l 20.

Example 3 Ethyl cinnamate (5.0 g) in CCl, (50 ml) was treated with a stream ml/min) of nitric oxide for 23 hours. The crude product was filtered through a column of florisil with benzene and the eluted material was recrystallized from diethyl ether-petroleum ether to give ethyl a-nitrocinnamate; m.p. 71-72.5.

Example 4 Ethyl 3,4-dimethoxycinnamate (5.0 g) in CO ml) was treated with a stream of nitric oxide for 53 hours. The crude product was filtered through a column of 150 g of florisil with benzene and benzene-ethyl acetate (9:1). and the eluted material was recrystallized from diethyl ether-petroleum ether to give ethyl a-nitro-3,4-dimethoxycinnamate; m.p. 9l-93.

Example 5 Ethyl 3-methoxy-4-acetoxycinnamate (5.0 g) in CCl (60 ml) was treated with a stream of nitric oxide for 43 hours. The crude product was filtered through a column of 150 g of florisil with benzene and benzene-ethyl acetate (9:1 and the eluted material was recrystallized from diethyl ether-petroleum ether to give ethyl a-nitro-3-methoxy-4acetoxycinnamate; m.p. 88-l03. Recrystallization from diethyl ether gave a product of m.p. l05-107.

Example 6 A solution of 1.0 g of ethyl a-nitro-3,4-dimethoxycinnamate in ml of glacial acetic acid containing 2 ml of acetic anhydride was hydrogenated at atmospheric pressure and room temperature using 0.5 g of 10 percent Pd/C catalyst. After the uptake was complete, the catalyst was filtered off and the solvent evaporated. The residual oil, containing N-acetyl-3,4-dimethoxyphenylalanine ethyl ester and 3,4-dimethoxyphenyl alanine ethyl ester was hydrolyzed by refluxing with 2 ml of 8 percent aqueous sodium hydroxide solution for 20 minutes. The cooled solution was extracted with methylene chloride and the aqueous layer was acidified to pH 2 with concentrated hydrochloric acid. After cooling in the refrigerator, the precipitated material was filtered, washed with water and dried at room temperature to give N-acetyl-3,4-dimethoxyphenylalanine monohydrate.

Additional material obtained from the filtrate by extraction with methylene chloride was 3,4-dimethoxyphenylalanine.

Example 7 Utilizing the procedure of Example 3, ethyl cinnamate was treated with nitrogen dioxide to yield ethyl a-nitro cinnamate.

Example 8 Utilizing the procedure of Example 3, ethyl 3-methoxy-4-hydroxy-cinnamate was treated with nitric oxide to yield ethyl a-nitro-3 methoxy-4-hydroxycinnamate.

Example 9 7 Utilizing the procedure of Example 8, with CC], being replaced by liquid S0 ethyl 3-methoxy-4- hydroxy cinnamate was treated with nitric oxide to yield ethyl a-nitro-3-methoxy-4-hydroxy-cinnamate.

Example 10 Example 11 Utilizing the procedure of Example 6, 1.0 g ethyl a-nitrocinnamate was hydrogenated in 75 ml of glacial acetic acid. containing 2 ml of acetic anhydride, using 0.5 g 10 percent Pd/C catalyst. N-acetyl-phenylalanine ethyl ester was obtained.

Example 12 Utilizing the procedure of Example 6, 1.0 g ethyl oz-nitro-S-methoxy-4-acetoxy cinnamate in 75 ml glacial acetic acid. containing 2 ml of acetic anhydride,

was hydrogenated using 0.5 g 10 percent Pd/C catalyst. N-acetyl-3-methoxy-4-acetoxyphenylalanine ethyl ester was obtained.

We claim:

l. A process for obtaining an a-nitro cinnamic acid 5 ester of the fommla:

wherein Y is an ester group convertible to a carboxy group by hydrolysis; and R and R are hydrogen or hydroxy or an ester or ether group convertible to a hydroxy group by hydrolysis; with the proviso that R and R are not both hydroxy; 20

comprising treating a compound of the formula:

wherein Y, R; and R are as above; with nitric oxide or nitrogen dioxide.

2. The process of claim 1 wherein said process is carried out in a chlorinated aliphatic hydrocarbon solvent or in an aromatic hydrocarbon solvent.

3. The process of claim 1 wherein said process is carried out at a temperature of about 0C. to the reflux temperature of the reaction mixture.

4. A compound of the formula:

Bil 2 wherein Y is selected from the group consisting of a carboxy, carb-loweralkoxy or carb-benzyloxy and R and R are selected from the group consisting of hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy or benzoyloxy.

5. The compound of claim 4 wherein said compound is ethyl oz-nitro-3,4-dimethoxycinnamate.

6. The compound of claim 4 wherein said compound is ethyl a-nitro-3-methoxy-4-acetoxy-cinnamate.

7. The compound of claim 4 wherein said compound is ethyl a-nitro-3-methoxy-4-hydroxy-cinnamate. 

2. The process of claim 1 wherein said process is carried out in a chlorinated aliphatic hydrocarbon solvent or in an aromatic hydrocarbon solvent.
 3. The process of claim 1 wherein said process is carried out at a temperature of about 0*C. to the reflux temperature of the reaction mixture.
 4. A compound of the formula:
 5. The compound of claim 4 wherein said compound is ethyl Alpha -nitro-3,4-dimethoxycinnamate.
 6. The compound of claim 4 wherein said compound is ethyl Alpha -nitro-3-methoxy-4-acetoxy-cinnamate.
 7. The compound of claim 4 wherein said compound is ethyl Alpha -nitro-3-methoxy-4-hydroxy-cinnamate. 